HOW DOES TRIUMEQ (DTG + ABC/3TC) COMPARE TO ATRIPLA (EFV/FTC/TDF) IN TREATMENT-NAÏVE PATIENTS? SINGLE STUDY DATA UP TO 144 WEEKS

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1 HOW DOES TRIUMEQ (DTG + ABC/3TC) COMPARE TO ATRIPLA (EFV/FTC/TDF) IN TREATMENT-NAÏVE PATIENTS? SINGLE STUDY DATA UP TO 144 WEEKS (Based on data from 144 week presentation) In studies supporting TRIUMEQ, DTG 50 mg + ABC 600 mg/3tc 300 mg were used. Bioequivalence has been demonstrated. ATRIPLA may not be licensed for initial use in all markets. SE/HIV/0009/17q

2 THERAPEUTIC INDICATIONS TRIUMEQ is indicated for the treatment of Human Immunodeficiency Virus (HIV) infected adults and adolescents above 12 years of age weighing at least 40 kg Hypersensitivity reaction is an uncommon but potentially life-threatening adverse event of abacavir, causally linked to carriage of the HLA-B*5701 genetic allele Before initiating treatment with TRIUMEQ, screening for carriage of the HLA-B*5701 allele should be performed in any HIV-infected patient, irrespective of racial origin TRIUMEQ should never be initiated in patients with a positive HLA-B*5701 status, nor in patients with a negative HLA-B*5701 status who had a suspected abacavir hypersensitivity reaction on a previous abacavir-containing regimen In studies supporting TRIUMEQ, DTG 50 mg + ABC 600 mg/3tc 300 mg were used. Bioequivalence has been demonstrated. TRIUMEQ Produktresumé 01/17

3 PHASE III DOLUTEGRAVIR TRIALS IN TREATMENT- NAÏVE ADULT SUBJECTS WITH HIV N=833 Non-inferiority, randomised, double-blind, double-dummy, multicentre study of: TRIUMEQ (QD) with ATRIPLA placebo ATRIPLA (QD) with TRIUMEQ placebo TRIUMEQ * vs ATRIPLA N=822 Non-inferiority, randomised, double-blind, double-dummy, multicentre study of: TIVICAY (QD) plus ISENTRESS placebo (BID) + 2 NRTIs ISENTRESS (BID) plus TIVICAY placebo (QD) + 2 NRTIs TIVICAY vs ISENTRESS N=484 Non-inferiority, randomised, active-controlled, multicentre, open-label study of: TIVICAY (QD) + 2 NRTIs PREZISTA (DRV/r [800 /100 mg] QD) + 2 NRTIs TIVICAY vs PREZISTA N=65 Randomized, single-centre, 2-part, open-label study of the single-dose PK of: TRIUMEQ (QD) ± Food ABC/3TC (600/300 mg) + DTG (50mg) (PK) TRIUMEQ vs DTG + ABC/3TC components Given as 2 x 400 mg tablets 3TC 300 mg were used. Bioequivalence has been demonstrated. ATRIPLA is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC TIVICAY is a registered trademark of the ViiV Healthcare Group of Companies ISENTRESS is a registered trademark of Merck & Co., Inc. PREZISTA is a registered trademark of Tibotec Pharmaceuticals Ltd. Walmsley S, et al. N Engl J Med 2013; 369: Raffi F, et al. Lancet 2013; 381: Raffi F, et al. Lancet Infect Dis 2013; 13: Clotet B, et al. Lancet 2014; 383: Weller S, et al. JAIDS 2014;66:

4 SINGLE STUDY DESIGN Treatment-naïve, HIV-1 positive HLA-B*5701 negative HIV-1 RNA 1000 c/ml Creatinine clearance >50 ml/min Stratified by baseline viral load and CD4 cell count TRIUMEQ QD plus ATRIPLA placebo (n=414) ATRIPLA QD plus TRIUMEQ placebo (n=419) TRIUMEQ QD ATRIPLA QD Screening Visit (~Day 21) Randomisation (Day 1) Analysis Week 48 Analysis Week 96 Analysis Week 144 Screening period Randomised phase Open-label phase Primary endpoint: Proportion with HIV-1 RNA <50 c/ml at Week 48, FDA snapshot analysis (-10% non-inferiority margin with pre-specified tests for superiority) In studies supporting TRIUMEQ, DTG 50 mg + ABC 600 mg/3tc 300 mg were used. Bioequivalence has been demonstrated. Adapted from Walmsley S, et al. N Engl J Med 2013; 369:

5 BASELINE CHARACTERISTICS Characteristic TRIUMEQ * QD (n=414) ATRIPLA QD (n=419) Median age, years (range) 36 (18-68) 35 (18-35) Female, n (%) 67 (16) 63 (15) African American / African Heritage, n (%) 98 (24) 99 (24) CDC class C, n (%) 18 (4) 17 (4) Baseline HIV-1 RNA Median (log 10 c/ml) >100,000 c/ml, n (%) 134 (32) 131 (31) Median CD4 cell count, cells/mm <200, % to <350, % to <500, % , % TC 300 mg were used. Adapted from Walmsley S, et al. N Engl J Med 2013; 369: Bioequivalence has been demonstrated. Adapted from Walmsley S, et al. N Engl J Med 2013; 369: (appendix)

6 Proportion with HIV-1 RNA <50 copies/ml TRIUMEQ * MAINTAINED STATISTICALLY SUPERIOR EFFICACY VS ATRIPLA UP TO 144 WEEKS TRIUMEQ demonstrated statistically superior efficacy vs ATRIPLA at 48, 96, and 144 weeks TRIUMEQ demonstrated rapid suppression of viral load vs ATRIPLA (28 days vs 84 days, respectively; P<0.0001) % 81% Week 48 adjusted difference in response (95% CI) 7.4% [2.5%, 12.3%]; P=0.003 TRIUMEQ QD (n=414) ATRIPLA QD (n=419) % non-inferiority margin with pre-specified tests for superiority TRIUMEQ Produktresumé 01/17 Adapted from Walmsley S, et al. N Engl J Med 2013; 369: Adapted from Walmsley S, et al. Poster presented at: 21st CROI Poster 543 Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a Week 80% 72% Week 96 adjusted difference in response (95% CI) 8.0% [2.3%, 13.8%]; P=0.006 TRIUMEQ : 71% ATRIPLA : 63% Week 144 adjusted difference in response (95% CI) 8.3% [2.0%, 14.6%]; P=0.010

7 Percent With HIV-1 RNA <50 c/ml TRIUMEQ * WAS EFFECTIVE REGARDLESS OF BASELINE VIRAL LOAD Week (1.0, 16.2) 7.6 (-3.9, 19.1) ,000 >100,000 Baseline plasma HIV-1 RNA, c/ml TRIUMEQ QD (n=414) ATRIPLA QD (n=419) 32% of treatmentnaïve patients had a baseline viral load >100,000 copies/ml P=0.831; test for homogeneity; P value confirms that there is no evidence of heterogeneity in treatment difference across the baseline stratification factors Walmsley S, et al. N Engl J Med 2013; 369: (appendix) Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a Adapted from Pappa K, et al. Abstract presented at: 54th ICAAC 2014

8 Adjusted mean change from baseline CD4+ cell count (cells/mm 3 ) TRIUMEQ * HAD STATISTICALLY SUPERIOR CD4 + T-CELL INCREASES VS ATRIPLA UP TO 144 WEEKS cells/mm cells/mm cells/mm 3b 332 cells/mm cells/mm 3 Week 48 difference in response (95% CI): 59% [33%, 84%]; P< cells/mm 3 TRIUMEQ QD (n=414) ATRIPLA QD (n=419) Week 96 difference in response (95% CI): 44% [14%, 74%]; P=0.004 Week 144 difference in response (95% CI): 47% [16%, 78%]; P=0.003 TRIUMEQ Week Produktresumé 01/17 Adapted from Walmsley S, et al. N Engl J Med 2013; 369: Adapted from Walmsley S, et al. Poster presented at: 21st CROI Poster 543 Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a

9 Proportion (%) of patients with AE leading to discontinuation FEWER DISCONTINUATIONS DUE TO ADVERSE EVENTS UP TO 144 WEEKS WITH TRIUMEQ * VS ATRIPLA Discontinuations due to AEs were 4% for TRIUMEQ vs 14% for ATRIPLA at Week TRIUMEQ QD (n=414) ATRIPLA QD (n=419) Week 48 Week 96 Week 144 Adapted from Walmsley S, et al. N Engl J Med 2013; 369: Adapted from Walmsley S, et al. Poster presented at: 21st CROI Poster 543 Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a

10 Proportion (%) of patients with AE leading to withdrawal TRIUMEQ * WAS GENERALLY BETTER TOLERATED VS ATRIPLA UP TO 144 WEEKS WITH FEWER DISCONTINUATIONS The incidence of psychiatric or nervous system disorders leading to withdrawal up to 144 weeks was <1% each for TRIUMEQ and 6%, 4% respectively for ATRIPLA 20 Common AEs leading to withdrawal by system organ class ( 2% in either arm) TRIUMEQ QD (n=414) ATRIPLA QD (n=419) <1 <1 <1 Psychiatric disorders Nervous system disorders Skin and subcutaneous tissue disorders General disorders and administration site conditions 2 Gastrointestinal disorders Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a

11 Mean Change from Baseline in Cr (μmol/l) THE EFFECT OF TRIUMEQ * ON SERUM CREATININE IS NOT CLINICALLY RELEVANT UP TO 144 WEEKS Small increases in serum creatinine occurred in the first week and remained stable up to 144 weeks These changes are not considered to be clinically relevant as the glomerular filtration rate is unchanged Mean change from baseline in creatinine up to 144 Weeks Weeks TRIUMEQ QD (n=414) ATRIPLA QD (n=419) Koteff J et al. Br J Clin Pharmacol. 2013;75(4): Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a

12 TRIUMEQ * HAS DEMONSTRATED A HIGH BARRIER TO RESISTANCE TO DATE No INI or NRTI resistance seen with TRIUMEQ up to 144 weeks TRIUMEQ QD (n=414) ATRIPLA QD (n=419) Week 48 Week 96 Week 144 Week 48 Week 96 Week 144 INI-resistant major substitution 0 0 ** 0 ** N/A N/A N/A NRTI major mutations NNRTI major mutations N/A N/A N/A **E157Q/P polymorphism detected in 1 patient with no significant change in INI phenotypic susceptibility Treatment emergent NRTI mutations detected: K65R Treatment-emergent NNRTI mutations detected: K101E (n=1), K103K/N (n=1), G190G/A (n=1) and K103N+G190G/A (n=1) Treatment-emergent NNRTI mutations detected: K101E (n=1); K103N (n=1); K103K/N (n=2), G190A (n=1) ; K103N+G190A (n=1) TRIUMEQ Produktresumé 01/17 Adapted from Walmsley S, et al. N Engl J Med 2013; 369: Adapted from Walmsley S, et al. N Engl J Med 2013; 369: (suppl appendix) Adapted from Walmsley S, et al. Poster presented at: 21st CROI Poster 543 Adapted from Pappa K, et al. Presented at: 54th ICAAC H-647a

13 SINGLE: SUMMARY TRIUMEQ * had statistically superior efficacy vs ATRIPLA 88% vs 81% remained undetectable at 48 weeks (P=0.003) 80% vs 72% remained undetectable at 96 weeks (P=0.006) 71% vs 63% remained undetectable at 144 weeks (P=0.010) TRIUMEQ is effective regardless of baseline viral load 83% of treatment-naïve patients with HIV-1 RNA >100,000 copies/ml remained undetectable at 48 weeks TRIUMEQ was still as effective as ATRIPLA in patients with high baseline viral loads at 96 weeks 69% of treatment-naïve patients with HIV-1 RNA >100,000 copies/ml remained undetectable at 144 weeks TRIUMEQ was generally better tolerated vs ATRIPLA with fewer discontinuations 2% vs 10% discontinued due to AEs at 48 weeks 3% vs 11% discontinued due to AEs at 96 weeks 4% vs 14% discontinued due to AEs at 144 weeks No INI or NRTI resistance up to 144 weeks with TRIUMEQ HLA-B* 5701 testing should be performed before initiating treatment with TRIUMEQ TRIUMEQ Produktresumé 01/17 Walmsley S, et al. N Engl J Med 2013; 369: Walmsley S, et al. Poster presented at: 21st CROI Poster 543 Pappa K, et al. Presented at: 54th ICAAC H-647a

14 SUPPLEMENTARY SAFETY INFORMATION

15 TRIUMEQ * HAD A LOWER IMPACT ON LIVER CHEMISTRY THAN ATRIPLA AT WEEK 48 Parameter/Criteria, (%) at Week 48 1 TRIUMEQ QD (n=414) ATRIPLA QD (n=419) Subjects meeting 1 FDA stopping criteria 10 (2) 39 (9) ALT 20xULN 0 0 ALT 5xULN 1 (<1) 2 (<1) ALT 3xULN 5 (1) 15 (4) Total bilirubin >1.5xULN 3 (<1) 2 (<1) Alkaline phosphatase >1.5xULN 1 (<1) 19 (5) ALT and/or AST >3xULN and total bilirubin >1.5xULN 0 0 Adapted from Walmsley S, et al. 52nd ICAAC Sept Abstract H-556b

16 Proportion (%) of patients with Grade 2 or higher ALT elevations TRIUMEQ * HAD A LOWER IMPACT ON LIVER CHEMISTRY THAN ATRIPLA AT WEEK 96 Grade 2 or higher ALT elevations were observed more commonly in the ATRIPLA arm than in the TRIUMEQ arm at Week TRIUMEQ QD (n=414) 15 ATRIPLA QD (n=419) Adapted from Walmsley S, et al. Poster presented at: 21st CROI Poster 543

17 ABBREVIATIONS 3TC, lamivudine ABC, abacavir AE, adverse event ALT, alanine amino transferase AST, aspartate amino transferase BID, twice daily c/ml, copies/ml CDC, Centres for Disease Control Cr, creatinine DRV/r, darunavir/ritonavir DTG, dolutegravir FDA, Food and Drug Administration HIV, human immunodeficiency virus HSR, hypersensitivity reaction INI, integrase inhibitor NRTI, nucleoside reverse transcriptase inhibitor QD, once daily RNA, ribonucleic acid ULN, upper limit of normal

18 MINIMIINFORMATION OCH RAPPORTERING AV BIVERKNINGAR TRIUMEQ (dolutegravir/abakavir/lamivudin) Rx, EF, ATC kod J05AR13 Detta läkemedel är föremål för utökad övervakning. Detta läkemedel är föremål för utökad övervakning.filmdragerad tablett innehållande 50 mg dolutegravir (som natrium), 600 mg abakavir (som sulfat), 300 mg lamivudin. Indikation: TRIUMEQ är avsett för behandling av humant immunbristvirus (hiv) hos vuxna och ungdomar över 12 år som väger mer än 40 kg. Innan behandling med abakavirinnehållande läkemedel påbörjas, ska screening för HLA-B*5701-allelen utföras på samtliga hiv-infekterade patienter, oavsett etniskt ursprung. Abakavir ska inte användas till patienter som man vet bär på HLA-B*5701-allelen. Kontraindikationer: Överkänslighet mot dolutegravir, abakavir eller lamivudin eller mot något hjälpämne. Samtidig administrering av dofetilid. Varningar och försiktighet: Behandling ska förskrivas av läkare med erfarenhet av behandling av hiv-infektion. Både abakavir och dolutegravir är förenade med en risk för överkänslighetsreaktioner. Överkänslighetsreaktioner har observerats oftare med abakavir, och några har varit livshotande, i sällsynta fall dödliga, när de inte har hanterats på rätt sätt. TRIUMEQ och andra misstänkta preparat måste därför omedelbart sättas ut vid tecken eller symtom på överkänslighetsreaktion. Om behandlingen med TRIUMEQ avslutas på grund av misstänkt överkänslighetsreaktion så får TRIUMEQ eller andra läkemedel som innehåller abakavir eller dolutegravir aldrig sättas in på nytt. Nedsatt njurfunktion: TRIUMEQ rekommenderas inte till patienter med kreatininclearance < 50 ml/min. Nedsatt leverfunktion: TRIUMEQ rekommenderas inte till patienter med måttligt eller allvarligt nedsatt leverfunktion. TRIUMEQ rekommenderas inte till patienter med resistens mot integrashämmare eller vid samtidig administrering av efavirenz, nevirapin, rifampicin och tipranavir/ritonavir. Interaktioner:Faktorer som minskar exponeringen för dolutegravir ska undvikas i närvaro av integrasklassresistens. Detta inkluderar samtidig administrering med läkemedel som minskar exponeringen för dolutegravir (t.ex. magnesium- och aluminiuminnehållande antacida, järn- och kalciumtillskott, multivitaminer och inducerande preparat, etravirin (utan boostade proteashämmare), tipranavir/ritonavir, rifampicin, johannesört och vissa antiepileptika). Dolutegravir ökar koncentrationen av metformin. Dosjustering av metformin ska övervägas vid insättning och utsättning av samtidig administrering av dolutegravir och metformin, för att bevara glykemisk kontroll. Metformin elimineras renalt och det är därför viktigt att kontrollera njurfunktionen vid samtidig administrering av dolutegravir. Denna kombination kan öka risken för laktacidos hos patienter med måttligt nedsatt njurfunktion. Biverkningar: De vanligaste rapporterade biverkningar som ansågs möjligen eller troligen relaterade till kombinationen dolutegravir och abakavir/lamivudin var illamående (12 %), insomni (7 %), yrsel (6 %) och huvudvärk (6 %). Abakavir-innehållande läkemedel, som TRIUMEQ, ska inte användas till patienter som man vet bär på HLA-B*5701- allelen. Vid tecken på överkänslighetsreaktion skall TRIUMEQ, omedelbart utsättas. För fullständig förskrivarinformation, se Datum för översyn av produktresumén 01/2017 TRIUMEQ är ett registrerat varumärke som tillhör företagsgruppen ViiV Healthcare. Om du vill rapportera en biverkan eller oönskad händelse kontakta biverkningsenheten på GlaxoSmithKline: Telefon: Postadress: Biverkningsenheten, GlaxoSmithKline, Box 516, Solna 18